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Oxygen Carriers Coursing Through Clinical Trials

By Karen Fleming-MichaelSpecial to American Forces Press Service

FORT DETRICK, Md., Nov. 10, 2005  When warfighters are bleeding severely on a battlefield, getting blood to them is tricky at best, because blood requires refrigeration and has a short shelf life. With this in mind, researchers for decades have been working on fluids, called hemoglobin-based oxygen carriers, that do blood's job of carrying oxygen.

Hemoglobin-based oxygen carriers (left, in an intravenous bag) can serves as a bridge until real blood (right) is available. HBOCs don't have to be typed and cross matched like blood and don't require a full-blown blood-donation program like the kind found in a hospital. Photo courtesy of Dr. Michael Dubick(Click photo for screen-resolution image);high-resolution image available.

"No oxygen equals cell death, tissue death," said Col. Robert Vandre, of the U.S. Army Combat Casualty Care Research Program here. "Once you get below a certain level of red cells in the blood, even if you can put in volume (with intravenous fluids), you're not going to have enough oxygen and everything starts shutting down. Then you start having inflammation problems and going into shock and everything falls apart."

To prevent that falling apart from happening, medical professionals' first choice for replacing lost blood will always be fresh, whole blood.

"The nice things about red cells, they not only carry oxygen, ... they also help in clotting blood," Vandre said. "If you look at a blood clot, it's red. That's because it's made up of red cells that act like little sandbags. Platelets, thrombin and fibrinogen are the glue that hold all the red cells together."

When red cells or whole blood just aren't available, a hemoglobin-based oxygen carrier, or HBOC, serves as a bridge until real blood is available. An HBOC, though an oxygen carrier, is not a blood replacement, said Dr. Michael Dubick, a senior research pharmacologist who manages resuscitation research at the U.S. Army Institute of Surgical Research, at Fort Sam Houston, Texas.

"They (HBOCs) don't do all the things that blood does and don't offer the clotting benefits present in platelets," he said. "But they buy you time until you can actually get a blood transfusion."

Anyone can receive an HBOC because everyone has hemoglobin, Vandre said. The fluid doesn't have to be typed and cross matched like blood and doesn't require a full-blown blood-donation program like the kind found in a hospital.

An HBOC may also help when wounded warfighters face long evacuation times, Dubick said.

"In Afghanistan, at times evacuation times were long. We've heard reports (that they were) from 12 to 36 hours. I think there was an anecdote of a helicopter being shot down at 14,000 feet, and it took time to get the people evacuated because they were still under fire," he said. "If you have longer evacuation times, perhaps the regular fluid they (medics) were carrying ... wouldn't be good enough. You don't have blood, but you do want to give them something like blood as soon as possible."

The Army invented the first HBOC at the since-shuttered Letterman Army Institute of Research, in San Francisco. "They first tried taking the hemoglobin out of the blood and using it to deliver oxygen, but straight hemoglobin is a bad idea," Vandre said. "It's so small that it leaked out of the blood vessels quickly. Not only did it not do the oxygen-carrying job, it leached out and made the skin turn color."

Once they linked hemoglobin molecules in big clumps, researchers moved past the leaking, but first-generation HBOCs had other problems. They raised the recipient's blood pressure, failing in clinical trials in Europe where nearly three times as many patients in the treatment group died compared to the control group, Dubick said.

No product has yet fully met the military's ideal of having a two-year shelf life, needing no refrigeration and having no limit on the number of units that can be given. However, today's second-generation HBOCs in clinical trials are faring much better than their predecessors, Vandre said. The grape-juice colored fluids are packaged in a bag similar to red blood cells so they don't weigh too much. There's little chance of allergic reactions because everyone has hemoglobin, which makes blood red. They do seem to cause the skin to turn yellow as the liver processes the HBOC, but that's a temporary side effect, Dubick said.

One HBOC, called PolyHeme, is already in clinical trials nationwide at trauma centers. In July, Brooke Army Medical Center, in San Antonio, began participating in the trial after getting permission from the secretary of the Army.

"The Army is participating in this trial because we need an HBOC in the pre-hospital arena on the battlefield, and we need to be involved in the development of the product so when the product is delivered we know and understand and are the experts of this product," said Col. Toney Baskin, a trauma surgeon and principal investigator for the trial at Brooke Army Medical Center.

Getting permission from the Army was one hurdle for the trial; getting community consent was another. A trauma patient doesn't know in advance that he's going to be a trauma patient, Vandre said.

"And the ones that need red cells or HBOC are the ones that are really, really badly hurt. You can't get (informed) consent from them (to use an investigational new drug), ... and sometimes you can't get immediate consent of the next of kin, so you have to get consent of the community," he said.

To gain community consent, officials at Brooke Army Medical Center explained the trial to the military community and some of the outlying areas that Brooke services.

"I think 87 percent of the people who attended said that they agreed with the study and approved the study," Dubick said. "On a personal basis, whether they would want to have the product themselves is another question." Organizers distributed bracelets for people to wear if they did not want to receive the product.

The Brooke portion of the trial is still ongoing, with a goal of enrolling 20 patients who are 18 or older, not pregnant and who have a systolic blood pressure (the number on top) less than 90 because of blood loss from blunt or penetrating trauma, said Baskin, who serves as chief of trauma and critical care of the Trauma Division at the U.S. Army Institute of Surgical Research and Brooke Army Medical Center.

"HBOC on the battlefield ... would provide that bridge of life to get the wounded soldier off that mountain back to the combat surgical hospital alive where hemorrhage control could be provided and blood volume restored with his or her vital organs still intact and functioning," he said.

Another take on an oxygen carrier still in its early stages is to use "microbubbles." Instead of using hemoglobin, the microbubbles are fluorocarbons, specifically "dodecafluoropentane," a mouthful to say as well as a cousin of Freon, the automobile air conditioning fluid. The substance is liquid at room temperature, but when placed in the body, it turns into bubbles.

"When the bubbles go to the lungs, they ... will actually suck in oxygen from your lungs and when they get out to the tissues they'll give off the oxygen," Vandre said. "They act much like an HBOC."

Studies using microbubbles in a laboratory setting show that three tablespoons carry as much oxygen as an average person's blood. Packaged as a liquid in a tiny vial, microbubbles appear to be very safe, Vandre said, and are used in such a low volume that a medic could carry them easily.

"If somebody was losing a lot of blood, the first thing to do is try to stop the bleeding, then give Hextend (a resuscitation fluid) to keep the volume up. If they're still not doing well because they lost too many red cells, then you'd give them this if red cells weren't available," he said. "Such a small amount can make such a big difference."

Currently, Vandre's program is evaluating 16 resuscitation products to find the best candidates to take to clinical trial. If microbubbles win, they could enter clinical trials by 2008.

Regardless of which product wins, the experts seem to agree that oxygen can make the difference between life and death in trauma cases.

"I have been in situations where patients have been losing blood, and blood was not available. Had there been an HBOC available, perhaps lives could have been saved," Baskin said.

(Karen Fleming-Michael is assigned to the U.S. Army Medical Research and Materiel Command.)